Artículo
Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars
Autor/es | Pingitore, Valeria
Martínez Bailén, Macarena Carmona Asenjo, Ana Teresa Mészáros, Zuzana Kulik, Natalia Slámová, Kristýna Křen, Vladimír Bojarová, Pavla Robina Ramírez, Inmaculada Moreno Vargas, Antonio José |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2022 |
Fecha de depósito | 2022-03-24 |
Publicado en |
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Resumen | Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and ... Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of β-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal β-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic β-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 × 104 times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A. |
Agencias financiadoras | Ministerio de Ciencia e Innovación (MICIN). España Ministerio de Economía y Competitividad (MINECO). España Junta de Andalucía Czech Science Foundation |
Identificador del proyecto | PID2020-116460RB-100
CTQ2016-77270-R FQM-345 GA21-01948L |
Cita | Pingitore, V., Martínez Bailén, M., Carmona Asenjo, A.T., Mészáros, Z., Kulik, N., Slámová, K.,...,Moreno Vargas, A.J. (2022). Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars. Bioorganic Chemistry, 120, 105650. |
Ficheros | Tamaño | Formato | Ver | Descripción |
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10.1016_j.bioorg.2022.105650.pdf | 3.975Mb | [PDF] | Ver/ | |